1. In this randomized controlled trial, among adolescent girls and young women, it was found that twice-yearly lenacapavir resulted in a significantly reduced human immunodeficiency virus (HIV) incidence.
2. Lenacapavir was associated with more injection-site reactions than emtricitabine-tenofovir isopropyl fumarate (F/TDF) and tenofovir alafenamide with emtricitabine (F/TAF).
Evidence Rating Level: 1 (Excellent)
Study Rundown: Globally, women account for approximately half of the 1.3 million new HIV infections that occur each year. Daily oral F/TDF is effective as pre-exposure prophylaxis (PrEP) when taken as directed, but adherence among women remains poor. Tenofovir alafenamide (TAF) is an HIV reverse transcriptase inhibitor with more rapid uptake by mononuclear cells than TDF and, when co-formulated with emtricitabine (F/TAF), can be administered in a smaller tablet than F/TDF. Lenacapavir is a multistage HIV-1 capsid inhibitor with a long half-life, allowing for administration by twice-yearly subcutaneous injection. Both agents have demonstrated high efficacy in preclinical studies and could potentially overcome current challenges regarding adherence. The present trial assessed the efficacy and safety of twice-yearly subcutaneous lenacapavir or daily oral F/TAF compared with daily oral F/TDF for HIV prevention among adolescent girls and young women. Lenacapavir reduced HIV incidence by 100% compared with both background HIV incidence and daily oral F/TDF. In contrast, F/TAF did not significantly reduce HIV incidence compared to background HIV incidence or F/TDF. The study was limited by its lack of longitudinal follow-up, with further monitoring for breakthrough HIV infection and delayed HIV seroconversion with lenacapavir use being warranted. Nevertheless, these findings show that twice-yearly lenacapavir could overcome current challenges with respect to adherence and improve PrEP use among women.
Click to read the study in NEJM
In-Depth [randomized controlled trial]: This phase three randomized-controlled trial compared the efficacy of twice-yearly subcutaneous lenacapavir or daily oral F/TAF for HIV prevention with daily oral F/TDF among adolescent girls and young women. Those 16 to 25 years of age who were sexually active with male partners, not using PrEP, and had unknown HIV status with no HIV testing within the previous three months were included. All participants underwent HIV testing; HIV-positive participants were referred for HIV care, while HIV-negative participants were randomly assigned in a 2:2:1 ratio to receive lenacapavir, F/TAF, or F/TDF. The primary efficacy outcome was the incidence of HIV infection. A total of 5,338 participants were included in the study, with 2,134 assigned to the lenacapavir group, 2,136 to the F/TAF group, and 1,068 to the F/TDF group. No incident HIV infections were observed in the lenacapavir group (0 per 100 person-years; 95% Confidence Interval [CI], 0.00 to 0.19), compared with 39 in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44 to 2.76) and 16 in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96 to 2.74). Lenacapavir reduced HIV incidence by 100% compared with both background HIV incidence (incidence rate ratio [IRR], 0.00; 95% CI, 0.00 to 0.04) and F/TDF (IRR, 0.00; 95% CI, 0.00 to 0.10). In contrast, F/TAF did not significantly reduce HIV incidence compared with background HIV incidence (IRR, 0.84; 95% CI, 0.55 to 1.28) or F/TDF (IRR, 1.20; 95% CI, 0.67 to 2.14). Efficacy was strongly associated with adherence, with adherence to F/TAF and F/TDF generally being poor; within the F/TAF group, participants with medium or high adherence were less likely to acquire HIV than those with low adherence. The percentage of participants with adverse events was generally similar across all three trial groups, apart from a higher incidence of injection-site reactions and a lower percentage of participants with nausea and vomiting in the lenacapavir group. In summary, twice-yearly lenacapavir resulted in a significantly lower HIV incidence than background HIV incidence and daily F/TDF, whereas daily F/TAF did not significantly reduce HIV incidence.
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